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In Hae Park, Sun-Young Kong, Youngmee Kwon, Min Kyeong Kim, Sung Hoon Sim, Jungnam Joo, Keun Seok Lee
Background: The PI3K/AKT/mTOR pathway is an important oncogenic driver in triple-negative breast cancer (TNBC). This study investigated the clinical efficacy and safety of the combination of gemcitabine and cisplatin with everolimus (GPE) in patients with metastatic TNBC. Methods: In phase I, we assessed the maximum tolerated dose (MTD) of GPE in metastatic TNBC patients. Then, using a seamless design, we conducted a randomized phase II trial to compare GPE to GP in terms of progression-free survival (PFS) and toxicity...
2018: Journal of Cancer
Hao Feng, Peng Jin, Hao Wu
Disease diagnosis using cell-free DNA (cfDNA) has been an active research field recently. Most existing approaches perform diagnosis based on the detection of sequence variants on cfDNA; thus, their applications are limited to diseases associated with high mutation rate such as cancer. Recent developments start to exploit the epigenetic information on cfDNA, which could have substantially wider applications. In this work, we provide thorough reviews and discussions on the statistical method developments and data analysis strategies for using cfDNA epigenetic profiles, in particular DNA methylation, to construct disease diagnostic models...
April 16, 2018: Briefings in Bioinformatics
Tomoyuki Koga, Bin Li, Javier M Figueroa, Bing Ren, Clark C Chen, Bob S Carter, Frank B Furnari
Background: Epidermal growth factor receptor (EGFR) variant III (vIII) is the most common oncogenic rearrangement in glioblastoma (GBM) generated by deletion of exons two to seven of EGFR. The proximal breakpoints occur in variable positions within the 123-kb intron one, presenting significant challenges in terms of PCR-based mapping. Molecular mechanisms underlying these deletions remain unclear. Methods: We determined the presence of EGFRvIII and its breakpoints for 29 GBM samples using quantitative polymerase chain reaction (qPCR), arrayed PCR mapping, Sanger sequencing, and whole genome sequencing (WGS)...
April 12, 2018: Neuro-oncology
Chi-Ju Kim, Juhee Park, Vijaya Sunkara, Tae-Hyeong Kim, Yongjin Lee, Kyusang Lee, Mi-Hyun Kim, Yoon-Kyoung Cho
The potential utility of circulating tumour DNA (ctDNA) in patient blood for cancer diagnostics and real-time monitoring of disease progression is highly recognized. However, the lack of automated and efficient methods for cell-free DNA (cfDNA) isolation from peripheral blood has remained a challenge for broader acceptance of liquid biopsy in general clinical settings. Here, we demonstrate a lab-on-a-disc system equipped with newly developed, electromagnetically actuated, and reversible diaphragm valves that allows fully automated and rapid (<30 min) isolation of cfDNA from whole blood (>3 ml) to achieve high detection sensitivity by minimizing the degradation of fragile ctDNA as well as contamination of wild-type DNA from abundant blood cells...
April 16, 2018: Lab on a Chip
Juan Sanchis, Sergio García-Blas, Luis Ortega-Paz, Ana Paula Dantas, Enrique Rodríguez, Lidia Abellán, Salvatore Brugaletta, Ernesto Valero, Gema Miñana, Manuel Garabito, África Corchón, Julio Núñez, Arturo Carratalá, Manel Sabaté
INTRODUCTION AND OBJECTIVES: Cell-free DNA (cfDNA) in ST-segment elevation myocardial infarction might originate from hyperactivated leukocytes at the coronary lesion. Our aim was to investigate the relationship between cfDNA and coronary reperfusion. METHODS: We studied 116 patients treated with primary angioplasty using thrombus aspiration. Coronary (during aspiration) and peripheral (at the end of the procedure) blood samples were drawn for cfDNA, as well as high-sensitivity troponin T and myeloperoxidase quantification...
April 11, 2018: Revista Española de Cardiología
M Rohan Fernando, Chao Jiang, Gary D Krzyzanowski, Wayne L Ryan
BACKGROUND: Plasma cell-free DNA (cfDNA) fragment size distribution provides important information required for diagnostic assay development. We have developed and optimized droplet digital PCR (ddPCR) assays that quantify short and long DNA fragments. These assays were used to analyze plasma cfDNA fragment size distribution in human blood. METHODS: Assays were designed to amplify 76,135, 490 and 905 base pair fragments of human β-actin gene. These assays were used for fragment size analysis of plasma cell-free, exosome and apoptotic body DNA obtained from normal and pregnant donors...
April 12, 2018: Clinica Chimica Acta; International Journal of Clinical Chemistry
Peter J Ferrandi, Brandon G Fico, Michael Whitehurst, Michael C Zourdos, Fanchen Bao, Katelyn M Dodge, Alexandra A Rodriguez, Gabriel Pena, Chun-Jung Huang
AIMS: Obesity is associated with lipid aggregation in adipocytes and macrophage infiltration, leading to increased oxidative stress and inflammation. Increased cell-free DNA (cfDNA) concentrations have been observed in clinical conditions of systemic inflammation. While the beneficial effects of regular physical activity on the release of circulating cfDNA still remain unknown, acute intense exercise has been shown to increase inflammatory cytokines and cfDNA concentrations in normal-weight individuals...
April 10, 2018: Life Sciences
Ismail Labgaa, Carlos Villacorta-Martin, Delia D'Avola, Amanda J Craig, Johann von Felden, Sebastiao N Martins-Filho, Daniela Sia, Ashley Stueck, Stephen C Ward, M Isabel Fiel, Milind Mahajan, Parissa Tabrizian, Swan N Thung, Celina Ang, Scott L Friedman, Josep M Llovet, Myron Schwartz, Augusto Villanueva
Cellular components of solid tumors including DNA are released into the bloodstream, but data on circulating-free DNA (cfDNA) in hepatocellular carcinoma (HCC) are still scarce. This study aimed at analyzing mutations in cfDNA and their correlation with tissue mutations in patients with HCC. We included 8 HCC patients treated with surgical resection for whom we collected paired tissue and plasma/serum samples. We analyzed 45 specimens, including multiregional tumor tissue sampling (n = 24), peripheral blood mononuclear cells (PMBC, n = 8), plasma (n = 8) and serum (n = 5)...
April 9, 2018: Oncogene
Caitlin M Stewart, Dana W Y Tsui
Cell-free DNA (cfDNA) was first identified in human plasma in 1948 and is thought to be released from cells throughout the body into the circulatory system. In cancer, a portion of the cfDNA originates from tumour cells, referred to as circulating-tumour DNA (ctDNA), and can contain mutations corresponding to the patient's tumour, for instance specific TP53 alleles. Profiling of cfDNA has recently become an area of increasing clinical relevance in oncology, in particular due to advances in the sensitivity of molecular biology techniques and development of next generation sequencing technologies, as this allows tumour mutations to be identified and tracked non-invasively...
March 11, 2018: Cancer Genetics
Jianlu Song, Zhili Yang
Metastatic follicular thyroid carcinoma (FTC), unresectable or resistance to radioactive iodine, is associated with poor survival. It is believed that this kind of FTC is driven by mutated genes. However, what kind of changes of genome and underlying mechanisms are elusive. The aim of this article is to understand whether there are somatic mutations in circulating cell-free tumor DNA (cfDNA) in a FTC patient with lung and bone metastases. A 55-year-old woman was diagnosed with FTC with bone and lung metastases...
January 2018: Journal of Circulating Biomarkers
Shiho Asaka, Akihiko Yoshizawa, Kazusa Saito, Yukihiro Kobayashi, Hiroshi Yamamoto, Tatsuya Negishi, Rie Nakata, Kazuyuki Matsuda, Akemi Yamaguchi, Takayuki Honda
Epidermal growth factor receptor (EGFR) mutations are associated with responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC). Our previous study revealed a rapid point-of-care system for detecting EGFR mutations. This system analyzes cell pellets from cytology specimens using droplet-polymerase chain reaction (d-PCR), and has a reaction time of 10 min. The present study aimed to validate the performance of the EGFR d-PCR assay using cell-free DNA (cfDNA) from supernatants obtained from cytology specimens...
March 27, 2018: International Journal of Oncology
Kazuki Kansaku, Yasuhisa Munakata, Nobuhiko Itami, Koumei Shirasuna, Takehito Kuwayama, Hisataka Iwata
This study examined the concentration of cell-free mitochondrial DNA (cf-mtDNA) in porcine follicular fluid (FF) and explored whether the cfDNA level in the culture medium could reflect mitochondrial dysfunction in cumulus cell-oocyte complexes (COCs). cfDNA concentration was higher in the fluid of small-sized follicles, compared to that in larger follicles. The length of cfDNA ranged from short (152 bp) to long (1,914 bp) mtDNA in FF, detected by polymerase chain reaction (PCR). cfDNA concentration in FF significantly correlated with the mtDNA copy number in FF but not with the number of one-copy gene (nuclear DNA) in FF...
April 3, 2018: Journal of Reproduction and Development
Hoyoon Lee, Wonhwi Na, Chanhee Park, Kyong Hwa Park, Sehyun Shin
Extraction of cell-free DNA (cfDNA), which exists at an extremely low concentration in plasma, is a critical process for either targeted-sensing or massive sequencing of DNAs. However, such small amount of DNA cannot be fully obtained without high-speed centrifugation (<20,000 g). Here, we developed a centrifugation-free cfDNA extraction method and system that utilizes an immiscible solvent under single low vacuum pressure throughout the entire process. It has been named Pressure and Immiscibility-Based EXtraction (PIBEX)...
April 3, 2018: Scientific Reports
Juozas Gordevičius, Algimantas Kriščiūnas, Daniel E Groot, Steven M Yip, Miki Susic, Andrew Kwan, Rafal Kustra, Anthony M Joshua, Kim N Chi, Art Petronis, Gabriel Oh
PURPOSE: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20-40% of patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance. EXPERIMENTAL DESIGN: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients...
April 3, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Qi Liu, Zhilei Ge, Xiuhai Mao, Guobao Zhou, Xiaolei Zuo, Juwen Shen, Jiye Shi, Jiang Li, Lihua Wang, Xiaoqing Chen, Chunhai Fan
Weak ligand-receptor recognition events are often amplified by recruiting multiple regulatory biomolecules to the action site in biological systems. However, signal amplification in in-vitro biomimetic systems generally lack the spatiotemporal regulation in vivo. Here we report a framework nucleic acids (FNA)-programmed strategy to develop valence-controlled signal amplifiers with high modularity for ultrasensitive biosensing. We demonstrated that the FNA-programmed signal amplifiers could recruit nucleic acids, proteins and inorganic nanoparticles in a stoichiometric manner...
March 30, 2018: Angewandte Chemie
Fatemeh Khatami, Bagher Larijani, Seyed Mohammad Tavangar
In molecular biology covalently closed circular DNAs are able to passthrough double layer of eukaryotic cellular membrane. Very recently the presence of circular extra chromosomal DNA (ecDNA) has been shown which are different in seventeen different types of cancers. In fact, ecDNA are the tricky way of oncogenes to increase their copy number. We hypothesis the presence of ecDNA in the blood of cancer patients as a subpopulation of liquid biopsy. On the occasion of their presence in blood they will be very beneficial to cover the small amount of cell frees DNA (cfDNA)...
May 2018: Medical Hypotheses
Caroline E McCoach, Collin M Blakely, Kimberly C Banks, Benjamin Levy, Ben M Chue, Victoria M Raymond, Anh Le, Christine E Lee, Joseph Diaz, Saiama N Waqar, W Thomas Purcell, Dara L Aisner, Kurtis D Davies, Richard B Lanman, Alice T Shaw, Robert C Doebele
PURPOSE: Patients with advanced non-small cell lung cancer (NSCLC) whose tumors harbor anaplastic lymphoma kinase ALK gene fusions benefit from treatment with ALK inhibitors (ALKi). Analysis of cell-free circulating tumor DNA (cfDNA) may provide a non-invasive way to identify ALK fusions and actionable resistance mechanisms without biopsy. EXPERIMENTAL DESIGN: The Guardant360 (G360) de-identified database of NSCLC cases was queried to identify 88 consecutive patients with 96 plasma-detected ALK fusions...
March 29, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Francesca Pezzuto, Luigi Buonaguro, Franco Maria Buonaguro, Maria Lina Tornesello
Hepatocellular carcinoma (HCC) is the third and the fifth leading cause of cancer related death worldwide in men and in women, respectively. HCC generally has a poor prognosis, with a very low 5-year overall survival, due to delayed diagnosis and treatment. Early tumour detection and timely intervention are the best strategies to reduce morbidity and mortality in HCC patients. Histological evaluation of liver biopsies is the gold standard for cancer diagnosis, although it is an invasive, time-consuming and expensive procedure...
March 28, 2018: International Journal of Molecular Sciences
Guoqiang Tan, Chang Chu, Xiujuan Gui, Jinyuan Li, Qiufang Chen
BACKGROUND: Circulating cell-free DNA (cfDNA) isolated from plasma or serum by noninvasive procedures can serve as a "liquid biopsy" and has potential as a biomarker for the tumor burden and survival prediction of breast cancer (BC). However, its prognostic value in patients with BC is currently under debate. The aim of this meta-analysis was to investigate the relationship between cfDNA and survival outcome. METHODS: We systematically searched PubMed, Embase, and Science Citation Index electronic databases for studies about the prognostic utility of cfDNA in patients with BC...
March 2018: Medicine (Baltimore)
Rodrigo A Toledo, Elena Garralda, Maria Mitsi, Tirso Pons, Jorge Monsech, Estela Vega, Alvaro Otero, Maria Isabel Albarran, Natalia Baños, Yolanda Duran, Victoria Bonilla, Francesca Sarno, Marta Camacho Artacho, Tania Sánchez-Pérez, Soria Perea, Rafael Alvarez, Alba De Martino Rodriguez, Daniel Lietha, Carmen Blanco-Aparicio, Antonio Cubillo, Orlando Dominguez, Jorge Martínez-Torrecuadrada, Manuel Hidalgo
BACKGROUND: Despite the wide use of antiangiogenic drugs in the clinical setting, predictive biomarkers of response to these drugs are still unknown. EXPERIMENTAL DESIGN: We applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens, including inhibitors to the VEGF:VEGFR2 pathway. We performed extensive functional experiments, including ectopic expression of VEGFR2 mutants in different cell lines, kinase and drug sensitivity assays, and cell- and patient-derived xenografts...
March 27, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
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